Given the very high burden malaria imposes on many developing countries, the overall objective of this proposal is to develop a P. falciparum malaria-specific immunogen that may be useful as an affordable and effective vaccine to prevent malaria. The current most effective malaria vaccine candidate (RTS,S/AS02A) is based on the use of a particulate carrier platform (the HBsAg) fused to malaria circumsporozoite (CS)-specific T and B cell epitopes. Current limitations of the RTS,S vaccine have been a requirement for reactogenic adjuvants and transient protection. A further potential complication is that the carrier is derived from a human pathogen, the hepatitis B virus (HBV). To circumvent these problems a non-human pathogen-derived carrier platform has been developed, specifically the core protein from the woodchuck hepadnavirus (WHcAg). Modified WHcAg particles will be used as the vaccine platform for several reasons: CS-WHcAg hybrid particles elicit extremely high levels of anti-CS antibodies;the immune tolerance to HBcAg and HBsAg in HBV chronic carriers (400 million worldwide) can be circumvented by the use of the WHcAg platform;and because CS-WHcAg hybrid particles can be made in bacteria, production of a vaccine will be relatively inexpensive. A preliminary CS-WHcAg hybrid particle has been developed that contains two neutralizing CS repeat epitopes inserted into the loop region (the insertion site that raises the highest titer anti-insert antibodies) and two "universal" malaria-specific T cell domains fused to the C-terminus. This CS-WHcAg hybrid particle is very immunogenic in mice and is capable of eliciting neutralizing anti-CS repeat antibodies that prevent P. falciparum/P. berghei hybrid sporozoite liver infection in vivo, therefore it is an ideal basis from which to develop a vaccine for human use. The strategy for developing an optimal malaria vaccine is divided into four aims: 1) incorporation of additional CS-derived B cell and T cell neutralizing epitopes;2) testing the protective efficacy of the vaccine candidates in a hybrid P. falciparum/P. berghei sporozoite model and developing the model to encompass additional P. falciparum epitopes;3) test recombinant and chemically linked "molecular adjuvants" for their ability to improve protective efficacy of the vaccine particles;and 4) determine optimal formulation, route and dosing of the chosen vaccine candidates. The combination of these two powerful technologies, the WHcAg-carrier platform and the P. falciparum/P. berghei hybrid sporozoite challenge model, will enable the production of a variety of CS-WHcAg hybrid particle immunogens that can be tested for protective efficacy in an in vivo infectious model system specific for P. falciparum malaria. Malaria is the world's most important lethal tropical parasitic disease (1.5 to 2.7 million deaths each year) with an estimated 300-500 million clinical new cases each year. The natural P. falciparum infection does not result in effective immunity, and malaria control efforts are being impeded by the spread of multiple drug resistant P. falciparum and the development of insecticide resistance by the anopheline mosquito vector. Therefore, a prophylactic vaccine is urgently needed to prevent further spread of this disease.